Nitroglycerin for Migraine

No longer recruiting at 1 trial location

Overseen By David J Altschul, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Montefiore Medical Center

Must not be taking: Vasoactive drugs, Phosphodiesterase inhibitors

Disqualifiers: Cardiac pathology, Severe pulmonary disease, Other headache conditions, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how nitroglycerin affects blood flow in people experiencing migraines. By observing changes in blood vessels during migraine attacks, researchers hope to gain insights that could lead to better treatments. Participants should have a documented migraine diagnosis, experience migraines at least twice a month, and have symptoms that don't improve with usual treatments. If migraines disrupt daily life and standard medications haven't helped, this trial might be a good fit.

As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could improve future migraine treatments.

Do I need to stop my current medications for the trial?

You may need to stop taking certain medications, especially if they are vasoactive drugs or similar to nitroglycerin. The trial excludes participants taking these types of medications.

What prior data suggests that this method is safe for migraine patients?

Research has shown that nitroglycerin, commonly used for heart issues, can also trigger migraine-like headaches in many individuals. Studies have found that administering nitroglycerin through an IV can cause headaches in up to 83% of those who suffer from migraines. These headaches are usually temporary and indicate that the medicine is working.

Nitroglycerin is generally safe, with most side effects being mild, such as headaches and skin rashes. However, it can sometimes lower blood pressure, causing dizziness or flushing. Despite these effects, most individuals tolerate the medication well when used correctly.

In summary, while nitroglycerin can cause some migraine-like symptoms, it is considered safe under medical supervision. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using nitroglycerin for migraines because it offers a unique delivery method directly targeting the arteries involved in headache pain. Unlike standard migraine treatments like oral medications, which can take time to work and affect the whole body, this approach delivers nitroglycerin right to the headache source through a catheter. This targeted method could potentially provide rapid relief by quickly widening specific blood vessels that cause migraines.

What evidence suggests that nitroglycerin might be an effective treatment for migraines?

Research has shown that nitroglycerin can cause migraine-like symptoms in most people who experience migraines. In one study, 82% of participants with migraines developed headaches after taking nitroglycerin. Another study found that nitroglycerin widens blood vessels, a change linked to migraine pain, observed in up to 80% of participants. Although nitroglycerin is not a treatment for migraines, understanding its effects on blood vessels aids researchers in finding new ways to manage migraines. Participants in this trial will receive nitroglycerin to study its effects on blood vessels and migraine symptoms. ^{6 7 8 9 10}

Who Is on the Research Team?

David J Altschul, MD

Principal Investigator

Montefiore Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with a neurologist-confirmed diagnosis of migraine, experiencing migraines at least twice a month and not responding to standard treatments. Participants must have had stable neurological exams in the past 6 months and be willing to undergo angiography. Pregnant women, children, those with severe pulmonary or cardiac conditions, recent caffeine or alcohol intake, or on certain medications are excluded.

Inclusion Criteria

You have not had any changes in your neurological exam in the past 6 months.

You have tried regular migraine treatments and still have severe, debilitating symptoms.

You have migraines that are different from other types of headaches.

Exclusion Criteria

Subjects who do not consent to participate

Subjects who are pregnant and children

You have had treatment or surgery on your brain for any brain issues in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-Angiography Evaluation

Participants undergo a clinic visit for history and physical evaluation, and complete a migraine questionnaire and headache log

1 day

1 visit (in-person)

Angiography and Immediate Post-Procedure Monitoring

Participants undergo angiography with nitroglycerin administration and vessel occlusion testing, followed by a 5-hour monitoring period

1 day

1 visit (in-person)

Follow-up

Participants complete a headache log and are monitored for migraine frequency and therapies utilized for 2 weeks post-angiogram

2 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Nitroglycerin

Trial Overview The study aims to understand migraine pain by using nitroglycerin-induced dilation of blood vessels during an angiogram to simulate migraine symptoms. Researchers will observe changes in vessel flow during headache attacks which could inform future treatment strategies.

How Is the Trial Designed?

Group I: Migraine Intervention Experimental Treatment 1 Intervention

A catheter will be placed in the symptomatic side external carotid artery and a diagnostic angiogram will be performed. The diameter of the occipital artery, superficial temporal artery and middle meningeal artery will be measured. Depending on the location of the headache superselective catheterization with microcatheter will be placed in either superficial temporal artery, occipital artery or middle meningeal artery. A volume of 50µg of nitroglycerin diluted in 10ml saline will be injected into the branch of interest dependent on laterality and location of symptoms over 30 seconds, to be delivered into these vessels only. 1 minute after superselective nitroglycerin injection the patient will be questioned as to whether the headache has been induced. A follow up diagnostic angiogram of the external carotid artery will be performed 3 minutes after injection. If there is no response to the lower 50µg, a dose of 150µg nitroglycerin in 10ml saline will be administered.

Who Is Running the Clinical Trial?

Montefiore Medical Center

Lead Sponsor

Trials

468

Recruited

599,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

Published Research Related to This Trial

Using a clinically relevant dose of glyceryl trinitrate (GTN) in awake rats, researchers successfully simulated a migraine model, showing significant upregulation of the nociceptive marker c-fos in the trigeminal nucleus, which is associated with migraine pain.

The model's specificity for migraine was confirmed by the attenuation of c-fos activation with sumatriptan, a common migraine treatment, making it a valuable tool for testing new anti-migraine drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A naturalistic glyceryl trinitrate infusion migraine model in the rat. Ramachandran, R., Bhatt, DK., Ploug, KB., et al.[2013]

Infusion of glyceryl trinitrate (GTN) in rats led to significant transcriptional changes in the trigeminal ganglia, with 15 genes showing altered expression, indicating a biological response to the treatment.

The analysis revealed pathways related to immune response, signal transduction, and neuroplasticity, suggesting that GTN infusion may activate mechanisms relevant to migraine development and could help in understanding migraine pathogenesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RNA Sequencing of Trigeminal Ganglia in Rattus Norvegicus after Glyceryl Trinitrate Infusion with Relevance to Migraine. Hougaard Pedersen, S., Maretty, L., Ramachandran, R., et al.[2023]

In a study involving 14 healthy volunteers, acetazolamide (Az) did not reduce the headache induced by glyceryl trinitrate (GTN), which is known to cause headaches and migraines.

Interestingly, the combination of GTN and Az led to more delayed headaches than GTN alone, suggesting that Az may trigger migraine-like symptoms even in individuals without a history of migraines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed migraine-like headache in healthy volunteers after a combination of acetazolamide and glyceryl trinitrate. Daugaard, D., Thomsen, LL., Iversen, HK., et al.[2016]

The pharmaceutical industry is losing interest in developing migraine drugs, partly due to the absence of reliable animal models for testing these medications.

The infusion of glyceryl trinitrate (GTN) is recognized as the most validated human migraine model, and efforts have been made to adapt this model for use in animals, highlighting the need for effective testing methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards a reliable animal model of migraine. Olesen, J., Jansen-Olesen, I.[2013]

The study aimed to create a rat model to predict migraine therapy by examining the effects of glyceryl trinitrate infusion on behaviors like burrowing, running wheel activity, and light sensitivity, but found that glyceryl trinitrate did not significantly alter these behaviors.

While light sensitivity showed some changes after glyceryl trinitrate infusion, these results were inconsistent and not repeatable, indicating that the current experimental setup may not be effective for studying headache behavior in rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infusion of low dose glyceryl trinitrate has no consistent effect on burrowing behavior, running wheel activity and light sensitivity in female rats. Christensen, SL., Petersen, S., Sørensen, DB., et al.[2017]

In a study involving 15 migraine patients, pre-treatment with prednisolone did not reduce the frequency of delayed migraine attacks caused by glyceryl trinitrate (GTN), but it significantly lowered the intensity of the delayed headache experienced after GTN infusion.

The results suggest that GTN may trigger migraine through inflammatory mediators, as prednisolone's effect on reducing headache intensity indicates a potential role of inflammation in both GTN-induced and spontaneous migraine attacks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prednisolone reduces nitric oxide-induced migraine. Tfelt-Hansen, P., Daugaard, D., Lassen, LH., et al.[2015]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/10524660/

Glyceryl trinitrate induces attacks of migraine without aura ... In the controls, the GTN-induced headache gradually disappeared, whereas in migraineurs peak headache intensity occurred at a mean time of 240 min post-infusion ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10039393/

Nitroglycerin as a model of migraine: Clinical and preclinical ... NTG mediates migraine-like behavioural and neuronal outcomes in rodents; validated by their response to therapeutics. •. Limitations: not effective in all ...

3. svn.bmj.com svn.bmj.com/content/6/2/180

Relationship between nitrate headache and outcome in ... Development of a nitrate headache by day 7 after stroke may be associated with improved activities of daily living and cognitive impairment at day 90.

4. journals.lww.com journals.lww.com/pain/fulltext/2020/09000/premonitory_symptoms_in_glyceryl_trinitrate.13.aspx

Premonitory symptoms in glyceryl trinitrate triggered... : PAIN Migraine-like headaches occurred in 28/34 (82.4%) migraineurs (GTN responders). After GTN, 26/28 (92.9%) responders, 6/6 (100%) nonresponders, and 13/24 (54.2%) ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1090380110002363

Oral nitric-oxide donor glyceryl-trinitrate induces ... In migraineurs, GTN administration was associated to a significant facilitation in temporal summation of pain (reduced TST and increased painful sensation) 60′, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7431147/

Premonitory symptoms in glyceryl trinitrate triggered ... Glyceryl trinitrate can provoke premonitory symptoms, namely yawning, nausea, photophobia, and concentration difficulties, which are most specific for an ...

7. mayoclinic.org mayoclinic.org/drugs-supplements/nitroglycerin-oral-route-sublingual-route/description/drg-20072863

Nitroglycerin (oral route, sublingual route) - Side effects & ... This medicine may cause headaches. These headaches are a sign that the medicine is working. Do not stop using the medicine or change the ...

8. sciencedirect.com sciencedirect.com/topics/nursing-and-health-professions/glyceryl-trinitrate

Glyceryl Trinitrate - an overview Glyceryl trinitrate is safe, since it causes only skin rashes and transient headache. Transdermal glyceryl trinitrate is effective as an analgesic co-adjuvant ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7528545/

Headache and non-headache symptoms provoked by ... Nitroglycerin administered intravenously at 0.5 mcg/kg/min over 20 minutes is able to provoke migraine headache in up to 83% of sufferers (11–13) and has been ...

10. go.drugbank.com go.drugbank.com/drugs/DB00727

Nitroglycerin: Uses, Interactions, Mechanism of Action Nitrate overdosage can result in following conditions: severe hypotension, persistent throbbing headache, vertigo, palpitation, visual disturbance, flushing and ...